Beyond ctDNA: A Review on Integrating Multi-Analyte Liquid Biopsies for Comprehensive Cancer Management

Background: Tissue biopsy is the established diagnostic standard in oncology; however, it is invasive, limited in spatial and temporal scope, and frequently impractical for serial monitoring. Liquid biopsy provides a minimally invasive and repeatable method for assessing tumour biology. Dependence on a singular analyte, such as ctDNA, may overlook clinically significant signals attributable to tumour heterogeneity, low shedding, and biological noise. Objective: To synthesise evidence that supports the use of multi-analyte liquid biopsy, which integrates ctDNA, circulating tumour cells (CTCs), extracellular vesicles/exosomes, microRNAs (miRNAs), and fragmentomics/epigenomics for purposes including screening, diagnosis, treatment selection, response assessment, and minimal residual disease (MRD) detection. Methods: This narrative review examines peer-reviewed studies, guidelines, and key trials across various analytes and disease contexts, focusing on integrative methodologies and their relevance in diverse environments, particularly in Sub-Saharan Africa. Results: ctDNA has been verified for the selection of targeted therapies in advanced NSCLC and for MRD risk stratification in colorectal cancer; its integration with CTCs enhances MRD detection and prognostic evaluation. DNA methylation and fragmentomics, including DELFI, improve the ability to find things early. Exosomal PD-L1 and phenotyped circulating tumour cells (CTCs) contribute to refined resistance profiling and immunotherapy monitoring. Also, circulating miRNAs make early-signal sensitivity higher. Multi-analyte panels, such as Cancer SEEK/DETECT-A and methylation-based MCED paired with fragmentomics, work better than single-analyte testing in some cases. Integrative models, on the other hand, give more accurate forecasts of outcomes. Conclusion: Multi-analyte liquid biopsy is emerging as an essential element of precision oncology. Standardised pre-analytics, harmonised analytics, and AI-driven integration are essential for improving therapeutic utility across various populations. It is important to prioritise future trials and implementation that is appropriate for the situation, even in Sub-Saharan Africa.